Respiratory infections strike millions of people each year and collectively cause more deaths than any single infectious disease (National Institute of Allergy and Infectious Diseases News Release, Oct. 30, 2000). Respiratory illness is most commonly caused by a viral infection.
Paramyxoviruses cause several respiratory diseases in humans and animals. Of these viruses, Respiratory Syncytial Virus (“RSV”), is an infectious agent that causes epidemics associated with extensive mortality and morbidity. The yearly epidemic nature of RSV infection is evident worldwide, but the incidence and severity of RSV disease in a given season vary by region (Hall, C. B., 1993, Contemp. Pediatr. 10:92–110). In temperate regions of the northern hemisphere, it usually begins in late fall and ends in late spring. Propagation of outbreaks is facilitated by the ease of transmission of RSV, which occurs by exposure to droplets of respiratory secretions of infected individuals (Hall et al., 1981, J. Pediatr. 99:101–103).
RSV is the leading cause of serious lower respiratory tract disease in infants and children (Feigen et al., eds., 1987, In: Textbook of Pediatric Infectious Diseases, W B Saunders, Philadelphia at pages 1653–1675; New Vaccine Development, Establishing Priorities, Vol. 1, 1985, National Academy Press, Washington D.C. at pages 397–409; and Ruuskanen et al., 1993, Curr. Probl. Pediatr. 23:50–79). By the age of three, virtually every child in America has had at least one respiratory infection caused by RSV. Of the eight million children under the age of five infected by RSV in the United States each year, approximately 5,000 die, another 100,000 are hospitalized, and 2.4 million are treated by a physician. Primary RSV infection occurs most often in children from 6 weeks to 2 years of age and uncommonly in the first 4 weeks of life during nosocomial epidemics (Hall et al, 1979, New Engl. J. Med. 300:393–396). Children at increased risk from RSV infection include preterm infants (Hall et al., 1979, New Engl. J. Med. 300:393–396) and children with bronchopulmonary dysplasia (Groothuis et al., 1988, Pediatrics 82:199–203), congenital heart disease (MacDonald et al., New Engl. J. Med. 307:397–400), congenital or acquired immunodeficiency (Ogra et al., 1988, Pediatr. Infect. Dis. J. 7:246–249; and Pohl et al., 1992, J. Infect. Dis. 165:166–169), and cystic fibrosis (Abman et al., 1988, J. Pediatr. 113:826–830). The fatality rate in infants with heart or lung disease who are hospitalized with RSV infection is 3%–4% (Navas et al., 1992, J. Pediatr. 121:348–354).
RSV infects adults as well as infants and children. In healthy adults, RSV causes predominantly upper respiratory tract disease. Several epidemics have been reported among nursing home patients and institutionalized young adults (Falsey, 1991, Infect. Control Hosp. Epidemiol. 12:602–608; and Garvie et al., 1980, Br. Med. J. 281:1253–1254). RSV may cause serious disease in immunosuppressed persons, particularly bone marrow transplant patients (Hertz et al., 1989, Medicine 68:269–281). RSV has also been reported as a problem in individuals undergoing cardiac, renal and lung transplants and in leukemia patients (Sinnot, et al., 1988, J. Infect. Dis. 158:650–651; Peigue-Lafeuille et al., 1990, Scand. J. Infect. Dis. 22:87–89; Doud et al, 1992, J. Heart Lung Transplant 11:77–79; and Whimbey et al., Clin. Infect. Dis. 21:376–379).
RSV is a non-segmented, negative-stranded RNA virus of the Paramyxoviridae family. RSV replicates in the cytoplasm of infected host cells and buds through the apical membrane, thereby acquiring its lipid envelope. The entire genetic material is associated with virus-encoded proteins, including the polymerase, which together form the nucleocapsid and are packaged in the virion (Collins et al., 1996, In: Virology, Raven Press at pp. 1313–1351). The 15,222 nucleotide genome encodes ten major proteins of which three, the F (fusion), G (attachment) and small hydrophobic SH (unknown function) proteins, are expressed on the virion surface and anchored in the lipid membrane (Collins et al., 1984, J. Virol. 49:572–578). Of the surface proteins, the F protein has emerged as a target for therapeutic intervention, largely in part because of its crucial role in viral entry. The F protein is thought to mediate fusion of virus and host cell membranes in a fashion that is common to many viruses; however, the mechanism of RSV viral fusion remains to be determined. Although antiviral strategy targeting the fusion pathway of viruses such as HIV has been successful, a need for successful antiviral strategies against RSV still exists.
Treatment options for established RSV disease are limited. Severe RSV disease of the lower respiratory tract requires considerable supportive care, including administration of humidified oxygen and respiratory assistance (Fields et al., eds., 1990, Fields Virology, 2nd ed., Vol. 1, Raven Press, New York at pages 1045–1072). Understanding of molecular aspects of the RSV life cycle is limited and has prevented a more fundamental, mechanism-based approach for antiviral drug discovery. As a consequence, most inhibitors of RSV disclosed to date have been discovered by a strategy of screening using a tissue cell culture assay.
The only clinically approved small-molecule therapy for the treatment of RSV infection is the antiviral agent ribavirin (marketed for RSV by ICN Pharmaceuticals, Costa Mesa, Calif.) (American Academy of Pediatrics Committee on Infectious Diseases, 1993, Pediatrics 92:501–504). Ribavirin is a nucleoside analog, but the precise mode of action remains to be established (Patterson et al., 1997, Rev. Infect. Dis. 12:1139–1146). The compound is effective in vitro against a broad spectrum of RNA viruses, and the inhibition of influenza virus by ribavirin is well-studied. This compound has been shown to be effective in the treatment of RSV pneumonia and bronchiolitis and has been shown to modify the course of severe RSV disease in immunocompetent children (Smith et al., 1991, New Engl. J. Med. 325:24–29). However, ribavirin has had limited use against RSV infection because it requires prolonged aerosol administration and because of concerns about its potential risks and side effects.
In addition to nucleoside analogs, several other agents have been investigated as anti-RSV molecules. Some agents have been characterized as inhibitors of RSV adsorption, although a detailed understanding of their mode of action remains to be elucidated. Examples of such agents are peptidic fusion inhibitors based on the identification of domains in the RSV F protein hypothesized to interact with each during stages of the fusion process. Because of the difficulties associated with identifying inhibitors of viral proteins and a limited range of targets, viruses such as RSV have also emerged as candidates for the development of therapeutics based on antisense oligonucleotides.
The difficulties in finding effective therapeutic agents has led to a focus on finding agents for the prevention of RSV infection. No vaccine is yet licensed for this indication. A major obstacle to vaccine development is safety. Several candidate RSV vaccines have been abandoned and others are under development (Murphy et al., 1994, Virus Res. 32:13–36), but even if safety issues are resolved, vaccine efficacy must also be improved. Recently, antibodies designed to induce passive immunization, such as Synagis® (a monoclonal antibody developed by MedImmune, Gaithersburg, Md.), have proved to be safer and more efficient than viral vaccines (Hemming et al., 1995, Clin. Microb. Rev. 8:22–33; Weltzin, 1998, Expert Opin. Invest. Drugs 7:1271–1283). However, even though the characterization of prophylactic agents has yielded promising results, effective therapeutic agents are still needed for the treatment of established RSV infection. Primary RSV infection and disease do not protect well against subsequent RSV disease (Henderson et al., 1979, New Engl. J. Med. 300:530–534).
Although many agents are being investigated, potent and specific, orally active antiviral agents have yet to be definitively characterized. So far, there is no ideal treatment for RSV infection, and there is no cure. Accordingly, novel therapeutics are needed that more effectively treat RSV infection. In particular, compounds for the treatment or prevention of RSV infection as a primary or secondary infection in patients as described above is contemplated herein.
In addition, RSV infection is often mistaken for human parainfluenza virus (“HPIV”) and influenza virus infection. (Collins et al., 1996, Virology pp. 1313–1351, Raven Press). HPIVs are also paramyxoviruses and are a common cause of lower respiratory tract disease in young children and can also cause serious lower respiratory tract disease with repeat infection (e.g., pneumonia, bronchitis, and bronchiolitis) among the elderly and those with compromised immune systems. HPIVs are spread from respiratory secretions through close contact with infected persons or contact with contaminated surfaces or objects. Influenza viruses are divided into three types, designated A, B, and C. Influenza types A and B are responsible for epidemics of respiratory illness that occur almost every winter and are often associated with increased rates for hospitalization and death. Influenza type C differs from types A and B in some important ways. Type C infection usually causes either a very mild respiratory illness or no symptoms at all; it does not cause epidemics and does not have the severe public health impact that influenza types A and B do. (See www.cdc.gov). Accordingly, novel therapeutics for the nonspecific treatment or prevention of respiratory illnesses caused by viral infection are also contemplated herein.